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Lung function improvements following inhaled indacaterol/glycopyrronium/mometasone furoate are independent of dosing time in asthma patients: a randomised trial

Jutta Beier, Henrik Watz, Zuzana Diamant, Jens M. Hohlfeld, Dave Singh, Pascale Pinot, Ieuan Jones, Hanns-Christian Tillmann
ERJ Open Research 2021 7: 00425-2020; DOI: 10.1183/23120541.00425-2020
Jutta Beier
1Insaf Respiratory Research Institute, Wiesbaden, Germany
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  • For correspondence: j.beier@insaf-wi.de
Henrik Watz
2Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research (DZL), Grosshansdorf, Germany
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Zuzana Diamant
3Dept of Respiratory Medicine and Allergology, Institute for Clinical Science, Skåne University Hospital, Lund, Sweden
4Dept of Microbiology, Immunology and Transplantation, KU Leuven, Catholic University of Leuven, Leuven, Belgium
5Dept of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre and QPS-NL, Groningen, The Netherlands
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Jens M. Hohlfeld
6German Center for Lung Research (BREATH), Hannover, Germany
7Dept of Respiratory Medicine, Hannover Medical School, Hannover, Germany
8Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
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  • ORCID record for Jens M. Hohlfeld
Dave Singh
9University of Manchester, Medicines Evaluation Unit, Manchester University NHS Foundation Trust, Manchester, UK
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Pascale Pinot
10Novartis Institutes for Biomedical Research, Basel, Switzerland
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Ieuan Jones
11Novartis Pharma AG, Basel, Switzerland
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Hanns-Christian Tillmann
10Novartis Institutes for Biomedical Research, Basel, Switzerland
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  • FIGURE 1
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    FIGURE 1

    Study design and participant inclusion. a) Study design. This was a randomised, placebo-controlled, double-blind, six-sequence, three-period, crossover study. b) Study disposition. Of 129 screened for enrolment in this study, 37 patients were randomised to one of six treatment sequences (each consisting of three treatment periods) in an allocation ratio of 1:1:1:1:1:1. For each sequence, a) six patients were planned to be randomised; b) as 37 patients were randomised, sequence 1 contained seven patients. 34 patients completed all three treatment periods. IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate. #: primary end-point mean forced expiratory volume in 1 s (FEV1) (L) (area under the curve from 0 to 24 h); ¶: two patients discontinued from the study during treatment period 1 due to subject/guardian decision; +: one patient experienced an asthma exacerbation and discontinued from the study on the first day of treatment period 3.

  • FIGURE 2
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    FIGURE 2

    Effect of morning or evening dosing of inhaled indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) on weighted mean forced expiratory volume in 1 s (FEV1) (area under the curve from 0 to 24 h (AUC0–24h)) versus placebo (pharmacodynamics (PD) analysis set). Comparison of morning or evening dosing of IND/GLY/MF on weighted mean FEV1 (mL) (AUC0–24h) with placebo in the PD analysis set. Parameters were analysed using a mixed model adjusting for period, treatment and sequence as fixed effect factors, and patient as a random effect. Data are presented as least squares means treatment difference (90% CI) compared with placebo. ref: reference.

  • FIGURE 3
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    FIGURE 3

    Effect of indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) on overall mean peak expiratory flow (L·min−1) (90% CI) over days 2–14 by treatment (pharmacodynamics analysis set). Parameters were calculated using a mixed-effects model including period, treatment (IND/GLY/MF morning, IND/GLY/MF evening, placebo), and sequence as fixed effects. Note: if a treatment period for an individual patient exceeded 14 days, the patient's peak expiratory flow (PEF) values contributed only up to day 14 for the respective period.

Tables

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  • TABLE 1

    Definition of treatment sequences

    Treatment period 1Treatment period 2Treatment period 3
    1ABC
    2BAC
    3CBA
    4CAB
    5ACB
    6BCA

    A: indacaterol acetate (IND)/glycopyrronium bromide (GLY)/mometasone furoate (MF) evening dose: placebo (a.m.) and IND/GLY/MF (p.m.); B: IND/GLY/MF morning dose: IND/GLY/MF (a.m.) and placebo (p.m.); C: placebo: placebo (a.m.) and placebo (p.m.).

    • TABLE 2

      Baseline participant demographics and characteristics (pharmacodynamics analysis set)

      Participants37
      Age years46.0 (18–72)
      Male21 (56.8)
      Body mass index kg·m−226.2±4.67
      Blood eosinophils ×109 cells·L−10.242±0.1588
      Race
       White35 (94.6)
       Other2 (5.4)
      Screening ICS category
       Low-dose31 (83.8)
       Medium-dose6 (16.2)
      Pre-bronchodilator FEV1 L2.9±0.72
      Post-bronchodilator FEV1 L3.4±0.81
      FEV1 pre-dose % predicted75.8 (60–96)
      Reversibility L0.5±0.21
      Reversibility %18.9 (12–52)
      Baseline morning# PEF L·min−1422.4±107.42
      Baseline evening# PEF L·min−1454.9±107.51

      Data are presented as n, mean (range), n (%) or mean±sd. ICS: inhaled corticosteroids; FEV1: forced expiratory volume in 1 s; PEF: peak expiratory flow. #: morning and evening PEF are defined as the first adequate results prior to dosing for each time point.

      • TABLE 3

        Comparison of peak expiratory flow (PEF) measured in the morning and evening after 14 days of treatment (pharmacodynamics analysis set)

        PEF L·min−1
        LS means (90% CI)LS means difference (90% CI)
        Morning mean
         IND/GLY/MF a.m. versus placebo#489.6 (456.2–523.1) versus 417.5 (384.1–450.9)72.1 (61.3–82.9)
         IND/GLY/MF p.m. versus placebo#504.4 (471.0–537.9) versus 417.5 (384.1–450.9)86.9 (76.1–97.8)
         IND/GLY/MF a.m. versus IND/GLY/MF p.m.489.6 (456.2–523.1) versus 504.4 (471.0–537.9)–14.8 (–25.6––4.1)
        Evening mean
         IND/GLY/MF a.m. versus placebo#522.0 (488.7–555.4) versus 449.0 (415.7–482.3)73.1 (61.9–84.2)
         IND/GLY/MF p.m. versus placebo#507.7 (474.3–541.0) versus 449.0 (415.7–482.3)58.7 (47.5–69.9)
         IND/GLY/MF a.m. versus IND/GLY/MF p.m.522.0 (488.7–555.4) versus 507.7 (474.3–541.0)14.4 (3.3–25.5)

        n=35, unless otherwise stated. Morning PEF assessments were performed 24 h after the last morning dose and 12 h after the last evening dose. Analogously, the evening PEF assessments were performed 24 h after the last evening dose and 12 h after the last morning dose. LS: least squares; IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate. #: n=36.

        • TABLE 4

          Incidence of treatment-emergent adverse events by preferred MedDRA term affecting >5% of patients (safety analysis set)

          IND/GLY/MF a.m.IND/GLY/MF p.m.PlaceboTotal
          Patients35353637
          Number of patients with ≥1 adverse event18 (51.4)23 (65.7)18 (50.0)32 (86.5)
          Headache5 (14.3)3 (8.6)7 (19.4)10 (27.0)
          Nasopharyngitis2 (5.7)2 (5.7)5 (13.9)8 (21.6)
          Oropharyngeal pain3 (8.6)4 (11.4)2 (5.6)7 (18.9)
          Cough1 (2.9)2 (5.7)1 (2.8)4 (10.8)
          Dysphonia2 (5.7)3 (8.6)1 (2.8)4 (10.8)
          Asthma1 (2.9)1 (2.9)1 (2.8)3 (8.1)
          Throat clearing1 (2.9)1 (2.9)0 (0.0)2 (5.4)

          Data are presented as n or n (%). MedDRA: Medical Dictionary for Regulatory Activities; IND: indacaterol acetate; GLY: glycopyrronium bromide; MF: mometasone furoate.

          Supplementary Materials

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            Supplementary material 00425-2020.SUPPLEMENT

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          Lung function improvements following inhaled indacaterol/glycopyrronium/mometasone furoate are independent of dosing time in asthma patients: a randomised trial
          Jutta Beier, Henrik Watz, Zuzana Diamant, Jens M. Hohlfeld, Dave Singh, Pascale Pinot, Ieuan Jones, Hanns-Christian Tillmann
          ERJ Open Research Apr 2021, 7 (2) 00425-2020; DOI: 10.1183/23120541.00425-2020

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          Lung function improvements following inhaled indacaterol/glycopyrronium/mometasone furoate are independent of dosing time in asthma patients: a randomised trial
          Jutta Beier, Henrik Watz, Zuzana Diamant, Jens M. Hohlfeld, Dave Singh, Pascale Pinot, Ieuan Jones, Hanns-Christian Tillmann
          ERJ Open Research Apr 2021, 7 (2) 00425-2020; DOI: 10.1183/23120541.00425-2020
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